Process of synthesizing alphatocopherol



Patented eb. 4,1941

m; FFICE PROCESS OF SYNTHESIZING ALPHA- TOCOPHEBOL Fritz von Werder, Darmstadt, Germany, nor

to Merck & (30., Inc., Rahway, N. 5., a corporation of New Jersey No Drawing. Application August 28, 1939, Serial No. 292,318. In Gey September 28, 1938 1 Claim.

This invention relates to a-tocopherol and to processes for its production. a

Certain processes for .the production of atocopherol have been previously recorded in the literature. Thus, Karrer, Fritzsche, Ringier and Salomon (Helvetica Chimica Acta XXI, pages 520-524, 1938) have reported its production by condensation of trimethylhydroquinone and phytyl bromide in the presence of anhydrous zinc chloride. Subsequently, Karrer and Demole (Schweizerische medizinische Wochenschrift, vol. 68, page 956, 1938) stated that aluminum chloride may also be used as the condensing agent for the reaction. Further, Smith, Ungnade and Pritchard (Science, vol. 88, page 3738, 1938) have reported that a-tocopherol was prepared from trimethylhydroquinone with phytyl bromide or phytadiene without the addition of a condensing agent.

Bergel, Jacob, Todd and Work (Nature, vol. 142, page 26, 1938) have reported that tocopherol may he produced by heating trimethylhydroquinone and phytol in the presence of zinc chloride, but no details concerning this conversion have been reported.

A process for the production of tocopheroi utilizing phytol itself as a reactant is desirable, but I have foundthat when trimethylhydroquinone is condensed with phytol in the presence of zinc chloride in accordance with the method mentioned by Bergel, Jacob, Todd and Work, a product is obtained which is deficient in vitamin- E activity in the animal test.

I have now found, however, that a highly ac tive vitamin-E product may be produced by con-= densing trimethylhydroquinone and phytol if a specific condensing agent, namely phosphorous pentoxide is employed. A careful comparison of the product obtained by a synthesis carried out in the presence of anhydrous zinc chloride according to Bergel, et al., as above mentioned, and

the product obtained by the new synthesis acv An explanation for these diiferences cannot be 5 definitely given at this time, but it is possible condensing agent employed, and that the differences in therapeutic efifectiveness result therefrom.

The following example is given to illustrate a preferred embodiment of my invention, but it will'be understood that certain modifications and adaptations may be madetherein without departing from the spirit of my invention and the scope of theappended claim.

Example About 5 gms. of trimethylhydroquinone and 10 gms. of phytol are dissolved in 20 cm. of absolute alcohol by gentle warming. This solution is added dropwise to about 10 gms. of phosphorous pentoxide while shaking and cooling, and is washed out with about 5 cm. of absolute alcohol. Hydrogen is passed through and the entire mixture is stirred for about V hour at room temperature, and then stirred while warming on the glycerine bath. The bath temperature is increased to-about 140, during the course of about 2 hours, whereby about 5-8 cm. of alcohol are distilled on the descending cooler. The mixture is stirred for about hour at 140". After cooling, about 100 cm? of'water and 280 cm. 012% caus tic soda solution are added dropwise with constant stirring. The oil separated is taken up in ether, the ether solution washed with about 5% caustic soda solution and water, dried, filtered and.

evaporated in vacuo to dryness. About 13.6 gms. of yellow oil are obtained as residue; its ultraviolet absorption spectrum shows a maximum of 290 u( iZL= graphically. The allophanate, prepared in the usual manner, melts at about I'm-171 0., its analytical values correspond to the formula CnHuOtN. and for ()D in chloroform it has a value of 0.67". The absorption spectrum of the allophanate is characterized by 2 maxima at 2 84 In a? =38) and 278 Inna? =35) and a minimum at 1 claim: Process for the-production or alphatoeopherol comprising. condensing trimethylhydroquinone' W23 phytol in the presence of phosphorous pent o e.

r'arrz vos wnannn. 

